Blockade of Rho/Rho-associated coiled coil-forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase-dependent manner

• Published in: Hepatology research 2008-08, Vol.38 (8), p.810-817
• Main Authors: Xue, Feng, Takahara, Terumi, Yata, Yutaka, Xia, Qiang, Nonome, Kazunobu, Shinno, Eiji, Kanayama, Masami, Takahara, Shiro, Sugiyama, Toshiro
• Format: Article
• Language: English
• Subjects: hepatocellular carcinoma; matrix metalloproteinase; metastasis; Rho/Rho-associated coiled coil-forming kinase
• ISSN: 1386-6346; 1872-034X
• DOI: 10.1111/j.1872-034X.2008.00333.x

Aim:  There is growing evidence that the Rho/Rho‐associated coiled coil‐forming kinase (ROCK) signaling pathway is upregulated in tumors and plays a key role in cancer invasion and metastasis. Our aim was to test the anticancer effects of Rho/ROCK inhibitor, Y‐27632, including possible mechanisms in a highly‐metastasizing hepatocellular carcinoma (HCC) mouse model on its secretion of matrix metalloproteinase (MMP) and tumor progression. Methods:  Following orthotopic implantation of CBO140C12 HCC tumor fragments into the liver of mice, the mice were randomly assigned to a Y‐27632‐treated group or control group. After treatment for 4 weeks, specimens were obtained to evaluate tumor size, metastases, and immunohistochemical findings. In vitro, we examined the effects of Y‐27632 and RhoC siRNA on MMP‐2 and ‐9 expressions, invasiveness, and apoptosis in cultured tumor cells. Results:  Both RhoA and RhoC were upregulated in HCC‐bearing livers, and Y‐27632 significantly inhibited not only tumor growth and intrahepatic metastasis (P